Scutellarein nanoparticles suppress colon cancer via PHB2-mediated mitophagy inhibition with modulatory effects on tumor-associated depression and osteotropic migration

Abstract

BACKGROUND: Colorectal cancer progression involves mitophagy, in which Prohibitin 2 (PHB2) regulates the PARL-PGAM5-PINK1 axis. Scutellarein has antitumor activity but poor bioavailability. We developed integrin αvβ3-targeted β-cyclodextrin-based scutellarein nanoparticles (Scu-NPs), which enhance the solubility, stability, and tumor-targeting of scutellarein, and investigated whether they suppress colon cancer via PHB2-mediated mitophagy inhibition and modulate tumor-associated depression and osteotropic migration. METHODS: PHB2 expression and mitochondrial localization were examined in colon cancer cells. SW480 cells with PHB2 overexpression were treated with Scu or Scu-NPs. Proliferation, migration, invasion, apoptosis, mitochondrial function, and mitophagy-related proteins were assessed. Subcutaneous xenografts, a chronic unpredictable mild stress tumor-depression model, behavioral tests, osteotropic migration assays, and bioinformatics were used. RESULTS: PHB2 was highly expressed and mitochondria-localized in colon cancer cells. Scu-NPs downregulated PHB2, increased PARL, decreased PGAM5, PINK1, Parkin, and LC3-II/LC3-I, and increased P62, indicating mitophagy inhibition. Scu-NPs induced mitochondrial dysfunction, ROS accumulation, apoptosis, and inhibited proliferation, migration, and invasion; PHB2 overexpression partially reversed these effects. In vivo, Scu-NPs suppressed xenograft growth and improved depressive-like behaviors, with PHB2 overexpression attenuating these effects. In vitro, Scu-NPs reduced colon cancer cell migration toward osteoblast-conditioned medium, whereas PHB2 overexpression partially reversed this effect. CONCLUSION: Scu-NPs suppress colon cancer by downregulating PHB2 and inhibiting mitophagy. PHB2 may serve as a shared molecular node linking tumor progression, depressive-like behaviors, and osteotropic migration, supporting Scu-NPs as a multi-target strategy.

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